P-glycoproteins in the Pathology and Treatment of Alzheimer's Disease

Raghad   H.   Aljohani; Nouf   F.   Alruwali; Shorooq   M.   Alrashedi; Somaya   M.   Yousef; Shahad   T.   Alobaidan; Nehal   M.   Elsherbiny; Hebatallah   H.   Atteia
doi:10.2174/0115701808293022240216070603
Abstract

Alzheimer's disease (AD), a central cause of dementia, is characterized by the accumulation of amyloid β-peptide (Aβ) peptides in the brain. P-glycoprotein (P-gp), a highly expressed protein in the BBB, plays a fundamental role in transporting Aβ from the brain to the blood and protecting the blood-brain barrier (BBB). The dysfunction or decreased abundance of this transporting protein is associated with the accumulation of Aβ, leading to dementia and cognitive deficits. In this review article, we consolidate the existing literature on the impact of P-gp in the pathophysiology and therapy of AD. Current evidence claims that p-gp is involved in AD pathology and that enhancing the activity of this transporter may be a promising therapeutic approach to hinder AD progression. There is also a growing interest in P-gp as a potential therapeutic target for AD. Hence, ongoing clinical trials and research should investigate P-gp inhibitor efficacy as a therapeutic approach for improving AD drug delivery to the brain and treatment outcomes.
Keywords: Amyloid β-peptide, P-glycoprotein, blood-brain barrier, Alzheimer’s disease, pathology, therapeutic targeting.
« Previous Next »
Graphical Abstract

[1]
Dementia by health world organization. 2020.  Available from:
          https://www.who.int/news-room/fact-sheets/detail/dementia(Accessed on December 9, 2020).

[2]
Bertram, L.; McQueen, M.B.; Mullin, K.; Blacker, D.; Tanzi, R.E. Systematic meta-analyses of Alzheimer disease genetic association studies: The AlzGene database. Nat. Genet.,  2007, 39(1), 17-23.
 [http://dx.doi.org/10.1038/ng1934] [PMID: 17192785]

[3]
Jellinger, K.A. Neuropathological aspects of Alzheimer disease, Parkinson disease and frontotemporal dementia. Neurodegener. Dis.,  2013, 13(2-3), 93-96.
 [PMID: 24008813]

[4]
Livingston, G.; Sommerlad, A.; Orgeta, V.; Costafreda, S.G.; Huntley, J.; Ames, D.; Ballard, C.; Banerjee, S.; Burns, A.; Cohen-Mansfield, J.; Cooper, C.; Fox, N.; Gitlin, L.N.; Howard, R.; Kales, H.C.; Larson, E.B.; Ritchie, K.; Rockwood, K.; Sampson, E.L.; Samus, Q.; Schneider, L.S.; Selbæk, G.; Teri, L.; Mukadam, N. Dementia prevention, intervention, and care. Lancet,  2017, 390(10113), 2673-2734.
 [http://dx.doi.org/10.1016/S0140-6736(17)31363-6] [PMID: 28735855]

[5]
Povova, J.; Ambroz, P.; Bar, M.; Pavukova, V.; Sery, O.; Tomaskova, H.; Janout, V. Epidemiological of and risk factors for Alzheimer’s disease: A review. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub.,  2012, 156(2), 108-114.
 [http://dx.doi.org/10.5507/bp.2012.055] [PMID: 22837131]

[6]
Suresh, S.; Singh, S. A.; Rushendran, R.; Vellapandian, C.; Prajapati, B. Alzheimer’s disease: The role of extrinsic factors in its development, an investigation of the environmental enigma. Front. Neurol.,  2023, 14, 1303111.
 [http://dx.doi.org/10.3389/fneur.2023.1303111] [PMID: 38125832]

[7]
Andersson, J.; Oudin, A.; Sundström, A.; Forsberg, B.; Adolfsson, R.; Nordin, M. Road traffic noise, air pollution, and risk of dementia: Results from the Betula project. Environ. Res.,  2018, 166, 334-339.
 [http://dx.doi.org/10.1016/j.envres.2018.06.008] [PMID: 29909174]

[8]
Kumar, N; Chourasiya, S; Kumar, A  Nath, BJECJ Assessment of ozone and nitrogen oxides variations in urban region of Patna.  India,  2022, 34, 170-192.
 [http://dx.doi.org/10.1080/10406026.2021.1957588]

[9]
Jung, C.R.; Lin, Y.T.; Hwang, B.F. Ozone, particulate matter, and newly diagnosed Alzheimer’s disease: A population-based cohort study in Taiwan. J. Alzheimers Dis.,  2015, 44(2), 573-584.
 [http://dx.doi.org/10.3233/JAD-140855] [PMID: 25310992]

[10]
Cassereau, J.; Ferré, M.; Chevrollier, A.; Codron, P.; Verny, C.; Homedan, C.; Lenaers, G.; Procaccio, V.; May-Panloup, P.; Reynier, P. Neurotoxicity of insecticides. Curr. Med. Chem.,  2017, 24(27), 2988-3001.
 [http://dx.doi.org/10.2174/0929867324666170526122654] [PMID: 28552054]

[11]
Voorhees, J.R.; Remy, M.T.; Erickson, C.M.; Dutca, L.M.; Brat, D.J.; Pieper, A.A. Occupational-like organophosphate exposure disrupts microglia and accelerates deficits in a rat model of Alzheimer’s disease. NPJ Aging Mech. Dis.,  2019, 5(1), 3.
 [http://dx.doi.org/10.1038/s41514-018-0033-3] [PMID: 30701080]

[12]
Notarachille, G.; Arnesano, F.; Calò, V.; Meleleo, D. Heavy metals toxicity: Effect of cadmium ions on amyloid beta protein 1–42. Possible implications for Alzheimer’s disease. Biometals,  2014, 27(2), 371-388.
 [http://dx.doi.org/10.1007/s10534-014-9719-6] [PMID: 24557150]

[13]
Colomina, M.T.; Peris-Sampedro, F. Aluminum and Alzheimer’s Disease. Adv. Neurobiol.,  2017, 18, 183-197.
 [http://dx.doi.org/10.1007/978-3-319-60189-2_9] [PMID: 28889268]

[14]
Martins, A.C., Jr; Gubert, P.; Villas Boas, G.R.; Meirelles Paes, M.; Santamaría, A.; Lee, E.; Tinkov, A.A.; Bowman, A.B.; Aschner, M. Manganese-induced neurodegenerative diseases and possible therapeutic approaches. Expert Rev. Neurother.,  2020, 20(11), 1109-1121.
 [http://dx.doi.org/10.1080/14737175.2020.1807330] [PMID: 32799578]

[15]
Bihaqi, S.W.; Zawia, N.H. Enhanced taupathy and AD-like pathology in aged primate brains decades after infantile exposure to lead (Pb). Neurotoxicology,  2013, 39, 95-101.
 [http://dx.doi.org/10.1016/j.neuro.2013.07.010] [PMID: 23973560]

[16]
del Pino, J.; Zeballos, G.; Anadón, M.J.; Moyano, P.; Díaz, M.J.; García, J.M.; Frejo, M.T. Cadmium-induced cell death of basal forebrain cholinergic neurons mediated by muscarinic M1 receptor blockade, increase in GSK-3β enzyme, β-amyloid and tau protein levels. Arch. Toxicol.,  2016, 90(5), 1081-1092.
 [http://dx.doi.org/10.1007/s00204-015-1540-7] [PMID: 26026611]

[17]
Wang, H.; Zhang, L.; Abel, G.M.; Storm, D.R.; Xia, Z. Cadmium exposure impairs cognition and olfactory memory in male C57BL/6 mice. Toxicol. Sci.,  2018, 161(1), 87-102.
 [http://dx.doi.org/10.1093/toxsci/kfx202] [PMID: 29029324]

[18]
Suresh, S.; Vellapandian, C. Cyanidin ameliorates bisphenol A-induced Alzheimer’s disease pathology by restoring Wnt/β-catenin signaling Cascade: An in vitro study. Mol. Neurobiol.,  2023, 2023, 3672.
 [http://dx.doi.org/10.1007/s12035-023-03672-6] [PMID: 37843801]

[19]
Liu, S.; Dashper, S.G.; Zhao, R. Association between oral bacteria and alzheimer’s disease: A systematic review and Meta-analysis. J. Alzheimers Dis.,  2023, 91(1), 129-150.
 [http://dx.doi.org/10.3233/JAD-220627] [PMID: 36404545]

[20]
Goldhardt, O.; Freiberger, R.; Dreyer, T.; Willner, L.; Yakushev, I.; Ortner, M.; Förstl, H.; Diehl-Schmid, J.; Milz, E.; Priller, J.; Ramirez, A.; Magdolen, V.; Thaler, M.; Grimmer, T. Herpes simplex virus alters Alzheimer’s disease biomarkers: A hypothesis paper. Alzheimers Dement.,  2023, 19(5), 2117-2134.
 [http://dx.doi.org/10.1002/alz.12834] [PMID: 36396609]

[21]
Phuna, Z.X.; Madhavan, P. A closer look at the mycobiome in Alzheimer’s disease: Fungal species, pathogenesis and transmission. Eur. J. Neurosci.,  2022, 55(5), 1291-1321.
 [http://dx.doi.org/10.1111/ejn.15599] [PMID: 35048439]

[22]
Samadi, M.; Moradi, S.; Moradinazar, M.; Mostafai, R.; Pasdar, Y. Dietary pattern in relation to the risk of Alzheimer’s disease: A systematic review. Neurol. Sci.,  2019, 40(10), 2031-2043.
 [http://dx.doi.org/10.1007/s10072-019-03976-3] [PMID: 31240575]

[23]
Doorduijn, A.S.; van de Rest, O.; van der Flier, W.M.; Visser, M. de van der Schueren, M.A.E. Energy and protein intake of Alzheimer’s disease patients compared to cognitively Normal controls: Systematic review. J. Am. Med. Dir. Assoc.,  2019, 20(1), 14-21.
 [http://dx.doi.org/10.1016/j.jamda.2018.06.019] [PMID: 30100233]

[24]
García-Casares, N.; Gallego Fuentes, P.; Barbancho, M.Á.; López-Gigosos, R.; García-Rodríguez, A.; Gutiérrez-Bedmar, M. Alzheimer’s disease, mild cognitive impairment and Mediterranean diet. A systematic review and dose-response Meta-analysis. J. Clin. Med.,  2021, 10(20), 4642.
 [http://dx.doi.org/10.3390/jcm10204642] [PMID: 34682764]

[25]
Hossain, M.F.; Wang, N.; Chen, R.; Li, S.; Roy, J.; Uddin, M.G.; Li, Z.; Lim, L.W.; Song, Y.Q. Exploring the multifunctional role of melatonin in regulating autophagy and sleep to mitigate Alzheimer’s disease neuropathology. Ageing Res. Rev.,  2021, 67, 101304.
 [http://dx.doi.org/10.1016/j.arr.2021.101304] [PMID: 33610813]

[26]
Lucey, B.P. It’s complicated: The relationship between sleep and Alzheimer’s disease in humans. Neurobiol. Dis.,  2020, 144, 105031.
 [http://dx.doi.org/10.1016/j.nbd.2020.105031] [PMID: 32738506]

[27]
Selkoe, D.J. Alzheimer’s disease: Genes, proteins, and therapy. Physiol. Rev.,  2001, 81(2), 741-766.
 [http://dx.doi.org/10.1152/physrev.2001.81.2.741] [PMID: 11274343]

[28]
Ferreira-Vieira, T.H.; Guimaraes, I.M.; Silva, F.R.; Ribeiro, F.M. Alzheimer’s disease: Targeting the cholinergic system. Curr. Neuropharmacol.,  2016, 14(1), 101-115.
 [http://dx.doi.org/10.2174/1570159X13666150716165726] [PMID: 26813123]

[29]
Butterfield, D.A.; Swomley, A.M.; Sultana, R. Amyloid beta-peptide (1-42)-induced oxidative stress in Alzheimer disease: importance in disease pathogenesis and progression. Antioxid. Redox Signal.,  2014, 21(18), 2744-2757.
 [http://dx.doi.org/10.1089/ars.2012.5027] [PMID: 23249141]

[30]
Heneka, M.T.; Carson, M.J.; Khoury, J.E.; Landreth, G.E.; Brosseron, F.; Feinstein, D.L.; Jacobs, A.H.; Wyss-Coray, T.; Vitorica, J.; Ransohoff, R.M.; Herrup, K.; Frautschy, S.A.; Finsen, B.; Brown, G.C.; Verkhratsky, A.; Yamanaka, K.; Koistinaho, J.; Latz, E.; Halle, A.; Petzold, G.C.; Town, T.; Morgan, D.; Shinohara, M.L.; Perry, V.H.; Holmes, C.; Bazan, N.G.; Brooks, D.J.; Hunot, S.; Joseph, B.; Deigendesch, N.; Garaschuk, O.; Boddeke, E.; Dinarello, C.A.; Breitner, J.C.; Cole, G.M.; Golenbock, D.T.; Kummer, M.P. Neuroinflammation in Alzheimer’s disease. Lancet Neurol.,  2015, 14(4), 388-405.
 [http://dx.doi.org/10.1016/S1474-4422(15)70016-5] [PMID: 25792098]

[31]
Sivamaruthi, B.S.; Raghani, N.; Chorawala, M.; Bhattacharya, S.; Prajapati, B.G.; Elossaily, G.M.; Chaiyasut, C. NF-κB pathway and its inhibitors: A promising frontier in the management of alzheimer’s disease. Biomedicines,  2023, 11(9), 2587.
 [http://dx.doi.org/10.3390/biomedicines11092587] [PMID: 37761028]

[32]
Zhu, H.; Bai, Y.; Wang, G.; Su, Y.; Tao, Y.; Wang, L.; Yang, L.; Wu, H.; Huang, F.; Shi, H.; Wu, X. Hyodeoxycholic acid inhibits lipopolysaccharide-induced microglia inflammatory responses through regulating TGR5/AKT/NF-κB signaling pathway. J. Psychopharmacol.,  2022, 36(7), 849-859.
 [http://dx.doi.org/10.1177/02698811221089041] [PMID: 35475391]

[33]
Yang, G.; Hu, Y.; Qin, X.; Sun, J.; Miao, Z.; Wang, L.; Ke, Z.; Zheng, Y. Micheliolide attenuates neuroinflammation to improve cognitive impairment of Alzheimer’s disease by inhibiting NF-κB and PI3K/Akt signaling pathways. Heliyon,  2023, 9(7), e17848.
 [http://dx.doi.org/10.1016/j.heliyon.2023.e17848] [PMID: 37456020]

[34]
Molina-Salinas, G.; Rodríguez-Chávez, V.; Langley, E.; Cerbon, M. Prolactin-induced neuroprotection against excitotoxicity is mediated via PI3K/AKT and GSK3β/NF-κB in primary cultures of hippocampal neurons. Peptides,  2023, 166, 171037.
 [http://dx.doi.org/10.1016/j.peptides.2023.171037] [PMID: 37301481]

[35]
Yang, S.; Magnutzki, A.; Alami, N.O.; Lattke, M.; Hein, T.M.; Scheller, J.S.; Kröger, C.; Oswald, F.; Yilmazer-Hanke, D.; Wirth, T.; Baumann, B. IKK2/NF-κB activation in astrocytes reduces amyloid β deposition: A process associated with specific microglia polarization. Cells,  2021, 10(10), 2669.
 [http://dx.doi.org/10.3390/cells10102669] [PMID: 34685649]

[36]
Hayden, M.S.; West, A.P.; Ghosh, S. NF-κB and the immune response. Oncogene,  2006, 25(51), 6758-6780.
 [http://dx.doi.org/10.1038/sj.onc.1209943] [PMID: 17072327]

[37]
Vogelgesang, S.; Cascorbi, I.; Schroeder, E.; Pahnke, J.; Kroemer, H.K.; Siegmund, W.; Kunert-Keil, C.; Walker, L.C.; Warzok, R.W. Deposition of Alzheimer’s?? -amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans. Pharmacogenetics,  2002, 12(7), 535-541.
 [http://dx.doi.org/10.1097/00008571-200210000-00005] [PMID: 12360104]

[38]
Chorawala, M.R.; Shah, A.C.; Pandya, A.J.; Kothari, N.R.; Prajapati, B.G. Symptoms and conventional treatments of Alzheimer’s disease. In: Alzheimer’s Disease and Advanced Drug Delivery Strategies; Academic Press, 2024; pp. 213-234.
 [http://dx.doi.org/10.1016/B978-0-443-13205-6.00009-1]

[39]
Sharma, K. Cholinesterase inhibitors as Alzheimer’s therapeutics (Review). Mol. Med. Rep.,  2019, 20(2), 1479-1487.
 [PMID: 31257471]

[40]
Pooladgar, P.; Sakhabakhsh, M.; Taghva, A.; Soleiman-Meigooni, S. Donepezil beyond Alzheimer’s Disease? A narrative review of therapeutic potentials of donepezil in different diseases. Iran. J. Pharm. Res.,  2022, 21(1), e128408.
 [http://dx.doi.org/10.5812/ijpr-128408] [PMID: 36942075]

[41]
Santos, G.S.; Sinoti, S.B.P.; de Almeida, F.T.C.; Silveira, D.; Simeoni, L.A.; Gomes-Copeland, K.K.P. Use of galantamine in the treatment of Alzheimer’s disease and strategies to optimize its biosynthesis using the in vitro culture technique. Plant Cell Tissue Organ Cult.,  2020, 143(1), 13-29.
 [http://dx.doi.org/10.1007/s11240-020-01911-5]

[42]
Nguyen, K.; Hoffman, H.; Chakkamparambil, B.; Grossberg, G.T. Evaluation of rivastigmine in Alzheimer’s disease. Neurodegener. Dis. Manag.,  2021, 11(1), 35-48.
 [http://dx.doi.org/10.2217/nmt-2020-0052] [PMID: 33198569]

[43]
Stazi, M.; Wirths, O. Chronic memantine treatment ameliorates behavioral deficits, neuron loss, and impaired neurogenesis in a model of Alzheimer’s disease. Mol. Neurobiol.,  2021, 58(1), 204-216.
 [http://dx.doi.org/10.1007/s12035-020-02120-z] [PMID: 32914393]

[44]
Beshir, S.A.; Aadithsoorya, A.M.; Parveen, A.; Goh, S.S.L.; Hussain, N.; Menon, V.B. Aducanumab therapy to treat Alzheimer’s disease: A narrative review. Int. J. Alzheimers Dis.,  2022, 2022, 1-10.
 [http://dx.doi.org/10.1155/2022/9343514] [PMID: 35308835]

[45]
Lloret, A.; Esteve, D.; Monllor, P.; Cervera-Ferri, A.; Lloret, A. The effectiveness of vitamin E treatment in Alzheimer’s disease. Int. J. Mol. Sci.,  2019, 20(4), 879.
 [http://dx.doi.org/10.3390/ijms20040879] [PMID: 30781638]

[46]
Mielech, A.; Puścion-Jakubik, A.; Markiewicz-Żukowska, R.; Socha, K. Vitamins in Alzheimer’s disease: Review of the latest reports. Nutrients,  2020, 12(11), 3458.
 [http://dx.doi.org/10.3390/nu12113458] [PMID: 33187212]

[47]
Lange, K.W.; Guo, J.; Kanaya, S.; Lange, K.M.; Nakamura, Y.; Li, S. Medical foods in Alzheimer’s disease. Food Sci. Hum. Wellness,  2019, 8(1), 1-7.
 [http://dx.doi.org/10.1016/j.fshw.2019.02.002]

[48]
Zucchella, C.; Sinforiani, E.; Tamburin, S.; Federico, A.; Mantovani, E.; Bernini, S.; Casale, R.; Bartolo, M. The multidisciplinary approach to Alzheimer’s disease and dementia. A narrative review of non-pharmacological treatment. Front. Neurol.,  2018, 9, 1058.
 [http://dx.doi.org/10.3389/fneur.2018.01058] [PMID: 30619031]

[49]
Li, B.S.Y.; Chan, C.W.H.; Li, M.; Wong, I.K.Y.; Yu, Y.H.U. Effectiveness and safety of aromatherapy in managing behavioral and psychological symptoms of dementia: A mixed-methods systematic review. Dement. Geriatr. Cogn. Disord. Extra,  2021, 11(3), 273-297.
 [http://dx.doi.org/10.1159/000519915] [PMID: 35082824]

[50]
Miki, E. Effects of touch and massage care in advanced alzheimer patient: A pilot case report; Graduate School of Biomedical and Health Sciences: Hiroshima University, 2020. 
 [http://dx.doi.org/10.5742/MEWFM.2020.93819]

[51]
Raglio, A.; Pavlic, E.; Bellandi, D. Music listening for people living with dementia. J. Am. Med. Dir. Assoc.,  2018, 19(8), 722-723.
 [http://dx.doi.org/10.1016/j.jamda.2018.05.027] [PMID: 30056951]

[52]
Knekt, P.; Järvinen, R.; Rissanen, H.; Heliövaara, M.; Aromaa, A. Does sauna bathing protect against dementia? Prev. Med. Rep.,  2020, 20, 101221.
 [http://dx.doi.org/10.1016/j.pmedr.2020.101221] [PMID: 33088678]

[53]
Singh, B.; Parsaik, A.K.; Mielke, M.M.; Erwin, P.J.; Knopman, D.S.; Petersen, R.C.; Roberts, R.O. Association of mediterranean diet with mild cognitive impairment and Alzheimer’s disease: A systematic review and meta-analysis. J. Alzheimers Dis.,  2014, 39(2), 271-282.
 [http://dx.doi.org/10.3233/JAD-130830] [PMID: 24164735]

[54]
Avgerinos, K.I.; Egan, J.M.; Mattson, M.P.; Kapogiannis, D. Medium chain triglycerides induce mild ketosis and may improve cognition in alzheimer’s disease. A systematic review and meta-analysis of human studies. Ageing Res. Rev.,  2020, 58, 101001.
 [http://dx.doi.org/10.1016/j.arr.2019.101001] [PMID: 31870908]

[55]
Li, D.; Ma, J.; Wei, B.; Gao, S.; Lang, Y.; Wan, X. Effectiveness and safety of ginkgo biloba preparations in the treatment of Alzheimer’s disease: A systematic review and meta-analysis. Front. Aging Neurosci.,  2023, 15, 1124710.
 [http://dx.doi.org/10.3389/fnagi.2023.1124710] [PMID: 36960422]

[56]
Wang, S.; Liu, H.Y.; Cheng, Y.C.; Su, C.H. Exercise dosage in reducing the risk of dementia development: Mode, duration, and intensity—A narrative review. Int. J. Environ. Res. Public Health,  2021, 18(24), 13331.
 [http://dx.doi.org/10.3390/ijerph182413331] [PMID: 34948942]

[57]
Elzayat, E.M.; Shahien, S.A.; El-Sherif, A.A.; Hosney, M. Therapeutic potential of stem cells and acitretin on inflammatory signaling pathway-associated genes regulated by miRNAs 146a and 155 in AD-like rats. Sci. Rep.,  2023, 13(1), 9613.
 [http://dx.doi.org/10.1038/s41598-023-36772-3] [PMID: 37311848]

[58]
Korkmaz, A.; Reiter, R.J.; Topal, T.; Manchester, L.C.; Oter, S.; Tan, D.X. Melatonin: An established antioxidant worthy of use in clinical trials. Mol. Med.,  2009, 15(1-2), 43-50.
 [http://dx.doi.org/10.2119/molmed.2008.00117] [PMID: 19011689]

[59]
Merlo, S.; Caruso, G.I.; Korde, D.S.; Khodorovska, A.; Humpel, C.; Sortino, M.A. Melatonin activates anti-inflammatory features in microglia in a multicellular context: Evidence from organotypic brain slices and HMC3 cells. Biomolecules,  2023, 13(2), 373.
 [http://dx.doi.org/10.3390/biom13020373] [PMID: 36830742]

[60]
Cook, M.; Lin, H.; Mishra, S.K.; Wang, G.Y. BAY 11-7082 inhibits the secretion of interleukin-6 by senescent human microglia. Biochem. Biophys. Res. Commun.,  2022, 617(Pt 1), 30-35.
 [http://dx.doi.org/10.1016/j.bbrc.2022.05.090] [PMID: 35671608]

[61]
Lin, Y.Z.; Yao, S.; Veach, R.A.; Torgerson, T.R.; Hawiger, J. Inhibition of nuclear translocation of transcription factor NF-kappa B by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence. J. Biol. Chem.,  1995, 270(24), 14255-14258.
 [http://dx.doi.org/10.1074/jbc.270.24.14255] [PMID: 7782278]

[62]
El-Sahar, A.E.; Shiha, N.A.; El Sayed, N.S.; Ahmed, L.A. Alogliptin attenuates lipopolysaccharide-induced neuroinflammation in mice through modulation of TLR4/MYD88/NF-κB and miRNA-155/SOCS-1 signaling pathways. Int. J. Neuropsychopharmacol.,  2021, 24(2), 158-169.
 [http://dx.doi.org/10.1093/ijnp/pyaa078] [PMID: 33125461]

[63]
Sarnico, I.; Boroni, F.; Benarese, M.; Alghisi, M.; Valerio, A.; Battistin, L.; Spano, P.; Pizzi, M. Targeting IKK2 by pharmacological inhibitor AS602868 prevents excitotoxic injury to neurons and oligodendrocytes. J. Neural Transm.,  2008, 115(5), 693-701.
 [http://dx.doi.org/10.1007/s00702-007-0016-1] [PMID: 18197358]

[64]
Kong, F.; Jiang, X.; Wang, R.; Zhai, S.; Zhang, Y.; Wang, D. Forsythoside B attenuates memory impairment and neuroinflammation via inhibition on NF-κB signaling in Alzheimer’s disease. J. Neuroinflammation,  2020, 17(1), 305.
 [http://dx.doi.org/10.1186/s12974-020-01967-2] [PMID: 33059746]

[65]
Youssef, M.; Ibrahim, A.; Akashi, K.; Hossain, M.S. PUFA-plasmalogens attenuate the LPS-induced nitric oxide production by inhibiting the NF-kB, p38 MAPK and JNK pathways in microglial cells. Neuroscience,  2019, 397, 18-30.
 [http://dx.doi.org/10.1016/j.neuroscience.2018.11.030] [PMID: 30496826]

[66]
Shehata, M.K.; Ismail, A.A.; Kamel, M.A. Combined donepezil with astaxanthin via nanostructured lipid carriers effective delivery to brain for alzheimer’s disease in rat model. Int. J. Nanomedicine,  2023, 18, 4193-4227.
 [http://dx.doi.org/10.2147/IJN.S417928] [PMID: 37534058]

[67]
Uddin, F.; Rudin, C.M.; Sen, T. CRISPR gene therapy: Applications, limitations, and implications for the future. Front. Oncol.,  2020, 10, 1387.
 [http://dx.doi.org/10.3389/fonc.2020.01387] [PMID: 32850447]

[68]
Rawal, S.; Khodakiya, A.; Prajapati, B.G. Nanotechnology-based delivery for CRISPR-Cas 9 cargo in Alzheimer’s disease. In: Alzheimer’s Disease and Advanced Drug Delivery Strategies; Academic Press, 2024; pp. 139-152.
 [http://dx.doi.org/10.1016/B978-0-443-13205-6.00012-1]

[69]
Hanafy, A.S.; Schoch, S.; Lamprecht, A. CRISPR/CAS9 delivery potentials in alzheimer’s disease management: A mini review. Pharmaceutics,  2020, 12(9), 801.
 [http://dx.doi.org/10.3390/pharmaceutics12090801] [PMID: 32854251]

[70]
Du, Y.; Liu, Y.; Hu, J.; Peng, X.; Liu, Z. CRISPR/Cas9 systems: Delivery technologies and biomedical applications; Asian J. Pharma. Sci, 2023. 

[71]
György, B.; Lööv, C.; Zaborowski, M.P.; Takeda, S.; Kleinstiver, B.P.; Commins, C.; Kastanenka, K.; Mu, D.; Volak, A.; Giedraitis, V.; Lannfelt, L.; Maguire, C.A.; Joung, J.K.; Hyman, B.T.; Breakefield, X.O.; Ingelsson, M. CRISPR/Cas9 mediated disruption of the Swedish APP allele as a therapeutic approach for early-onset Alzheimer’s disease. Mol. Ther. Nucleic Acids,  2018, 11, 429-440.
 [http://dx.doi.org/10.1016/j.omtn.2018.03.007] [PMID: 29858078]

[72]
Park, H.; Oh, J.; Shim, G.; Cho, B.; Chang, Y.; Kim, S.; Baek, S.; Kim, H.; Shin, J.; Choi, H.; Yoo, J.; Kim, J.; Jun, W.; Lee, M.; Lengner, C.J.; Oh, Y.K.; Kim, J. In vivo neuronal gene editing via CRISPR–Cas9 amphiphilic nanocomplexes alleviates deficits in mouse models of Alzheimer’s disease. Nat. Neurosci.,  2019, 22(4), 524-528.
 [http://dx.doi.org/10.1038/s41593-019-0352-0] [PMID: 30858603]

[73]
Sun, J.; Carlson-Stevermer, J.; Das, U.; Shen, M.; Delenclos, M.; Snead, A.M.; Koo, S.Y.; Wang, L.; Qiao, D.; Loi, J.; Petersen, A.J.; Stockton, M.; Bhattacharyya, A.; Jones, M.V.; Zhao, X.; McLean, P.J.; Sproul, A.A.; Saha, K.; Roy, S. CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage. Nat. Commun.,  2019, 10(1), 53.
 [http://dx.doi.org/10.1038/s41467-018-07971-8] [PMID: 30604771]

[74]
Komor, A.C.; Kim, Y.B.; Packer, M.S.; Zuris, J.A.; Liu, D.R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature,  2016, 533(7603), 420-424.
 [http://dx.doi.org/10.1038/nature17946] [PMID: 27096365]

[75]
Offen, D.; Rabinowitz, R.; Michaelson, D.; Ben-Zur, T. Towards gene-editing treatment for alzheimer’s disease: ApoE4 allele-specific knockout using a CRISPR cas9 variant. Cytotherapy,  2018, 20(5), S18.
 [http://dx.doi.org/10.1016/j.jcyt.2018.02.036]

[76]
Holstege, H.; van der Lee, S.J.; Hulsman, M.; Wong, T.H.; van Rooij, J.G.J.; Weiss, M.; Louwersheimer, E.; Wolters, F.J.; Amin, N.; Uitterlinden, A.G.; Hofman, A.; Ikram, M.A.; van Swieten, J.C.; Meijers-Heijboer, H.; van der Flier, W.M.; Reinders, M.J.T.; van Duijn, C.M.; Scheltens, P. Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: A clinical interpretation strategy. Eur. J. Hum. Genet.,  2017, 25(8), 973-981.
 [http://dx.doi.org/10.1038/ejhg.2017.87] [PMID: 28537274]

[77]
Knupp, A.; Mishra, S.; Martinez, R.; Braggin, J.E.; Szabo, M.; Kinoshita, C.; Hailey, D.W.; Small, S.A.; Jayadev, S.; Young, J.E. Depletion of the AD risk gene SORL1 selectively impairs neuronal endosomal traffic independent of amyloidogenic APP processing. Cell Rep.,  2020, 31(9), 107719.
 [http://dx.doi.org/10.1016/j.celrep.2020.107719] [PMID: 32492427]

[78]
Bhardwaj, S.; Kesari, K.K.; Rachamalla, M.; Mani, S.; Ashraf, G.M.; Jha, S.K.; Kumar, P.; Ambasta, R.K.; Dureja, H.; Devkota, H.P.; Gupta, G.; Chellappan, D.K.; Singh, S.K.; Dua, K.; Ruokolainen, J.; Kamal, M.A.; Ojha, S.; Jha, N.K. CRISPR/Cas9 gene editing: New hope for Alzheimer’s disease therapeutics. J. Adv. Res.,  2022, 40, 207-221.
 [http://dx.doi.org/10.1016/j.jare.2021.07.001] [PMID: 36100328]

[79]
Correia, A.C.; Monteiro, A.R.; Silva, R.; Moreira, J.N.; Sousa, Lobo J.M.; Silva, A.C. Lipid nanoparticles strategies to modify pharmacokinetics of central nervous system targeting drugs: Crossing or circumventing the blood–brain barrier (BBB) to manage neurological disorders. Adv. Drug Deliv. Rev.,  2022, 189, 114485.
 [http://dx.doi.org/10.1016/j.addr.2022.114485] [PMID: 35970274]

[80]
Chen, Y.P.; Chou, C.M.; Chang, T.Y.; Ting, H.; Dembélé, J.; Chu, Y.T.; Liu, T.P.; Changou, C.A.; Liu, C.W.; Chen, C.T. Bridging size and charge effects of mesoporous silica nanoparticles for crossing the blood–brain barrier. Front Chem.,  2022, 10, 931584.
 [http://dx.doi.org/10.3389/fchem.2022.931584] [PMID: 35880111]

[81]
Manzano, M.; Vallet-Regí, M. Mesoporous silica nanoparticles for drug delivery. Adv. Funct. Mater.,  2020, 30(2), 1902634.
 [http://dx.doi.org/10.1002/adfm.201902634]

[82]
Sivamaruthi, B.S.; Kapoor, D.U.; Kukkar, R.R.; Gaur, M.; Elossaily, G.M.; Prajapati, B.G.; Chaiyasut, C. Mesoporous silica nanoparticles: Types, synthesis, role in the treatment of alzheimer’s disease, and other applications. Pharmaceutics,  2023, 15(12), 2666.
 [http://dx.doi.org/10.3390/pharmaceutics15122666] [PMID: 38140007]

[83]
Pandey, P.K.; Sharma, A.K.; Rani, S.; Mishra, G.; Kandasamy, G.; Patra, A.K.; Rana, M.; Sharma, A.K.; Yadav, A.K.; Gupta, U. MCM-41 nanoparticles for brain delivery: Better choline-esterase and amyloid formation inhibition with improved kinetics. ACS Biomater. Sci. Eng.,  2018, 4(8), 2860-2869.
 [http://dx.doi.org/10.1021/acsbiomaterials.8b00335] [PMID: 33435009]

[84]
Halevas, E.; Mavroidi, B.; Nday, C.M.; Tang, J.; Smith, G.C.; Boukos, N.; Litsardakis, G.; Pelecanou, M.; Salifoglou, A. Modified magnetic core-shell mesoporous silica nano-formulations with encapsulated quercetin exhibit anti-amyloid and antioxidant activity. J. Inorg. Biochem.,  2020, 213, 111271.
 [http://dx.doi.org/10.1016/j.jinorgbio.2020.111271] [PMID: 33069945]

[85]
Singh, A.K.; Singh, S.S.; Rathore, A.S.; Singh, S.P.; Mishra, G.; Awasthi, R.; Mishra, S.K.; Gautam, V.; Singh, S.K. Lipid-coated MCM-41 mesoporous silica nanoparticles loaded with berberine improved inhibition of acetylcholine esterase and amyloid formation. ACS Biomater. Sci. Eng.,  2021, 7(8), 3737-3753.
 [http://dx.doi.org/10.1021/acsbiomaterials.1c00514] [PMID: 34297529]

[86]
Ribeiro, T.C.; Sábio, R.M.; Luiz, M.T.; de Souza, L.C.; Fonseca-Santos, B.; Cides da Silva, L.C.; Fantini, M.C.A.; Planeta, C.S.; Chorilli, M. Curcumin-loaded mesoporous silica nanoparticles dispersed in thermo-responsive hydrogel as potential alzheimer disease therapy. Pharmaceutics,  2022, 14(9), 1976.
 [http://dx.doi.org/10.3390/pharmaceutics14091976] [PMID: 36145723]

[87]
Liu, N.; Yang, C.; Liang, X.; Cao, K.; Xie, J.; Luo, Q.; Luo, H. Mesoporous silica nanoparticle-encapsulated Bifidobacterium attenuates brain Aβ burden and improves olfactory dysfunction of APP/PS1 mice by nasal delivery. J. Nanobiotechnology,  2022, 20(1), 439.
 [http://dx.doi.org/10.1186/s12951-022-01642-z] [PMID: 36207740]

[88]
Xu, L.; Guo, M.; Hung, C.T.; Shi, X.L.; Yuan, Y.; Zhang, X.; Jin, R.H.; Li, W.; Dong, Q.; Zhao, D. Chiral skeletons of mesoporous silica nanospheres to mitigate alzheimer’s β-Amyloid aggregation. J. Am. Chem. Soc.,  2023, 145(14), 7810-7819.
 [http://dx.doi.org/10.1021/jacs.2c12214] [PMID: 37002870]

[89]
Cummings, J.; Lee, G.; Ritter, A.; Sabbagh, M.; Zhong, K. Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement.,  2019, 5(1), 272-293.
 [http://dx.doi.org/10.1016/j.trci.2019.05.008] [PMID: 31334330]

[90]
Abbott, N.J.; Patabendige, A.A.K.; Dolman, D.E.M.; Yusof, S.R.; Begley, D.J. Structure and function of the blood–brain barrier. Neurobiol. Dis.,  2010, 37(1), 13-25.
 [http://dx.doi.org/10.1016/j.nbd.2009.07.030] [PMID: 19664713]

[91]
Hawkins, R.A. The blood-brain barrier and brain homeostasis. In: The blood-brain barrier and its role in cerebral edema; Hawkins, R.A.; Lajtha, W.N., Eds.; Springer, 2009; pp. 1-10.

[92]
Sweeney, M.D.; Zhao, Z.; Montagne, A.; Nelson, A.R.; Zlokovic, B.V. Blood-brain barrier: From physiology to disease and back. Physiol. Rev.,  2019, 99(1), 21-78.
 [http://dx.doi.org/10.1152/physrev.00050.2017] [PMID: 30280653]

[93]
Obermeier, B.; Daneman, R.; Ransohoff, R.M. Development, maintenance and disruption of the blood-brain barrier. Nat. Med.,  2013, 19(12), 1584-1596.
 [http://dx.doi.org/10.1038/nm.3407] [PMID: 24309662]

[94]
Wise, J.G. Catalytic transitions in the human MDR1 P-glycoprotein drug binding sites. Biochemistry,  2012, 51(25), 5125-5141.
 [http://dx.doi.org/10.1021/bi300299z] [PMID: 22647192]

[95]
Kim, Y.; Chen, J. Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation. Science,  2018, 359(6378), 915-919.
 [http://dx.doi.org/10.1126/science.aar7389] [PMID: 29371429]

[96]
Silva, R.; Vilas-Boas, V.; Carmo, H.; Dinis-Oliveira, R.J.; Carvalho, F.; de Lourdes Bastos, M.; Remião, F. Modulation of P-glycoprotein efflux pump: Induction and activation as a therapeutic strategy. Pharmacol. Ther.,  2015, 149, 1-123.
 [http://dx.doi.org/10.1016/j.pharmthera.2014.11.013] [PMID: 25435018]

[97]
Bikadi, Z.; Hazai, I.; Malik, D.; Jemnitz, K.; Veres, Z.; Hari, P.; Ni, Z.; Loo, T.W.; Clarke, D.M.; Hazai, E.; Mao, Q. Predicting P-glycoprotein-mediated drug transport based on support vector machine and three-dimensional crystal structure of P-glycoprotein. PLoS One,  2011, 6(10), e25815.
 [http://dx.doi.org/10.1371/journal.pone.0025815] [PMID: 21991360]

[98]
Cox, B.; Nicolaï, J.; Williamson, B. The role of the efflux transporter, P‐glycoprotein, at the blood–brain barrier in drug discovery. Biopharm. Drug Dispos.,  2023, 44(1), 113-126.
 [http://dx.doi.org/10.1002/bdd.2331] [PMID: 36198662]

[99]
Han, L. Modulation of the blood–brain barrier for drug delivery to brain. Pharmaceutics,  2021, 13(12), 2024.
 [http://dx.doi.org/10.3390/pharmaceutics13122024] [PMID: 34959306]

[100]
Deo, A.K.; Borson, S.; Link, J.M.; Domino, K.; Eary, J.F.; Ke, B.; Richards, T.L.; Mankoff, D.A.; Minoshima, S.; O’Sullivan, F.; Eyal, S.; Hsiao, P.; Maravilla, K.; Unadkat, J.D. Activity of P-glycoprotein, a β-amyloid transporter at the blood–brain barrier, is compromised in patients with mild Alzheimer disease. J. Nucl. Med.,  2014, 55(7), 1106-1111.
 [http://dx.doi.org/10.2967/jnumed.113.130161] [PMID: 24842892]

[101]
Cirrito, J.R.; Deane, R.; Fagan, A.M.; Spinner, M.L.; Parsadanian, M.; Finn, M.B.; Jiang, H.; Prior, J.L.; Sagare, A.; Bales, K.R.; Paul, S.M.; Zlokovic, B.V.; Piwnica-Worms, D.; Holtzman, D.M. P-glycoprotein deficiency at the blood-brain barrier increases amyloid- deposition in an Alzheimer disease mouse model. J. Clin. Invest.,  2005, 115(11), 3285-3290.
 [http://dx.doi.org/10.1172/JCI25247] [PMID: 16239972]

[102]
Hartz, A.M.S.; Zhong, Y.; Wolf, A.; LeVine, H., III; Miller, D.S.; Bauer, B. Aβ40 reduces P-glycoprotein at the blood–brain barrier through the ubiquitin–proteasome pathway. J. Neurosci.,  2016, 36(6), 1930-1941.
 [http://dx.doi.org/10.1523/JNEUROSCI.0350-15.2016] [PMID: 26865616]

[103]
Pfundstein, G.; Nikonenko, A.G.; Sytnyk, V. Amyloid precursor protein (APP) and amyloid β (Aβ) interact with cell adhesion molecules: Implications in Alzheimer’s disease and normal physiology. Front. Cell Dev. Biol.,  2022, 10, 969547.
 [http://dx.doi.org/10.3389/fcell.2022.969547] [PMID: 35959488]

[104]
Sadigh-Eteghad, S.; Sabermarouf, B.; Majdi, A.; Talebi, M.; Farhoudi, M.; Mahmoudi, J. Amyloid-beta: A crucial factor in Alzheimer’s disease. Med. Princ. Pract.,  2015, 24(1), 1-10.
 [http://dx.doi.org/10.1159/000369101] [PMID: 25471398]

[105]
Hampel, H.; Hardy, J.; Blennow, K.; Chen, C.; Perry, G.; Kim, S.H.; Villemagne, V.L.; Aisen, P.; Vendruscolo, M.; Iwatsubo, T.; Masters, C.L.; Cho, M.; Lannfelt, L.; Cummings, J.L.; Vergallo, A. The amyloid-β pathway in Alzheimer’s disease. Mol. Psychiatry,  2021, 26(10), 5481-5503.
 [http://dx.doi.org/10.1038/s41380-021-01249-0] [PMID: 34456336]

[106]
Zhang, Y.; Chen, H.; Li, R.; Sterling, K.; Song, W. Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future. Signal Transduct. Target. Ther.,  2023, 8(1), 248.
 [http://dx.doi.org/10.1038/s41392-023-01484-7] [PMID: 37386015]

[107]
Chai, A.B.; Hartz, A.M.S.; Gao, X.; Yang, A.; Callaghan, R.; Gelissen, I.C. New evidence for P-gp-mediated export of amyloid-β PEPTIDES in molecular, blood-brain barrier and neuronal models. Int. J. Mol. Sci.,  2020, 22(1), 246.
 [http://dx.doi.org/10.3390/ijms22010246] [PMID: 33383667]

[108]
Storck, S.E.; Hartz, A.M.S.; Bernard, J.; Wolf, A.; Kachlmeier, A.; Mahringer, A.; Weggen, S.; Pahnke, J.; Pietrzik, C.U. The concerted amyloid-beta clearance of LRP1 and ABCB1/P-gp across the blood-brain barrier is linked by PICALM. Brain Behav. Immun.,  2018, 73, 21-33.
 [http://dx.doi.org/10.1016/j.bbi.2018.07.017] [PMID: 30041013]

[109]
Weiss, N.; Miller, F.; Cazaubon, S.; Couraud, P.O. The blood-brain barrier in brain homeostasis and neurological diseases. Biochim. Biophys. Acta Biomembr.,  2009, 1788(4), 842-857.
 [http://dx.doi.org/10.1016/j.bbamem.2008.10.022] [PMID: 19061857]

[110]
Deane, R.; Sagare, A.; Zlokovic, B. The role of the cell surface LRP and soluble LRP in blood-brain barrier Abeta clearance in Alzheimer’s disease. Curr. Pharm. Des.,  2008, 14(16), 1601-1605.
 [http://dx.doi.org/10.2174/138161208784705487] [PMID: 18673201]

[111]
Wolf, A.; Bauer, B.; Hartz, A.M.S. ABC transporters and the Alzheimer’s disease enigma. Front. Psychiatry,  2012, 3, 54.
 [http://dx.doi.org/10.3389/fpsyt.2012.00054] [PMID: 22675311]

[112]
Ding, Y.; Zhong, Y.; Baldeshwiler, A.; Abner, E.L.; Bauer, B.; Hartz, A.M.S. Protecting P-glycoprotein at the blood–brain barrier from degradation in an Alzheimer’s disease mouse model. Fluids Barriers CNS,  2021, 18(1), 10.
 [http://dx.doi.org/10.1186/s12987-021-00245-4] [PMID: 33676539]

[113]
Hartz, A.M.S.; Zhong, Y.; Shen, A.N.; Abner, E.L.; Bauer, B. Preventing P-gp ubiquitination lowers aβ brain levels in an Alzheimer’s disease mouse model. Front. Aging Neurosci.,  2018, 10, 186.
 [http://dx.doi.org/10.3389/fnagi.2018.00186] [PMID: 29997495]

[114]
Mandelkow, E.M.; Mandelkow, E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb. Perspect. Med.,  2012, 2(7), a006247.
 [http://dx.doi.org/10.1101/cshperspect.a006247] [PMID: 22762014]

[115]
Guo, T.; Noble, W.; Hanger, D.P. Roles of tau protein in health and disease. Acta Neuropathol.,  2017, 133(5), 665-704.
 [http://dx.doi.org/10.1007/s00401-017-1707-9] [PMID: 28386764]

[116]
Sukanya, P. Dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitors: The quest for a disease-modifying treatment for alzheimer’s disease. In: In Deciphering Drug Targets for Alzheimer’s Disease; Springer: Singapore, 2023; pp. 69-94.
 [http://dx.doi.org/10.1007/978-981-99-2657-2_4]

[117]
Samudra, N.; Lane-Donovan, C.; VandeVrede, L.; Boxer, A.L. Tau pathology in neurodegenerative disease: disease mechanisms and therapeutic avenues. J. Clin. Invest.,  2023, 133(12), e168553.
 [http://dx.doi.org/10.1172/JCI168553] [PMID: 37317972]

[118]
Silva, M.C.; Haggarty, S.J. Tauopathies: Deciphering disease mechanisms to develop effective therapies. Int. J. Mol. Sci.,  2020, 21(23), 8948.
 [http://dx.doi.org/10.3390/ijms21238948] [PMID: 33255694]

[119]
Pradeepkiran, J.A.; Reddy, P.H. Phosphorylated tau targeted small-molecule PROTACs for the treatment of Alzheimer’s disease and tauopathies. Biochim. Biophys. Acta Mol. Basis Dis.,  2021, 1867(8), 166162.
 [http://dx.doi.org/10.1016/j.bbadis.2021.166162] [PMID: 33940164]

[120]
Sengupta, U.; Kayed, R. Amyloid β, Tau, and α-Synuclein aggregates in the pathogenesis, prognosis, and therapeutics for neurodegenerative diseases. Prog. Neurobiol.,  2022, 214, 102270.
 [http://dx.doi.org/10.1016/j.pneurobio.2022.102270] [PMID: 35447272]

[121]
Vyas, J.; Raytthatha, N.; Prajapati, B.G. Amyloid cascade hypothesis, tau synthesis, and role of oxidative stress in AD. In: Alzheimer’s Disease and Advanced Drug Delivery Strategies; Academic Press, 2024; pp. 73-92.
 [http://dx.doi.org/10.1016/B978-0-443-13205-6.00023-6]

[122]
De Felice, F.G.; Velasco, P.T.; Lambert, M.P.; Viola, K.; Fernandez, S.J.; Ferreira, S.T.; Klein, W.L. Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J. Biol. Chem.,  2007, 282(15), 11590-11601.
 [http://dx.doi.org/10.1074/jbc.M607483200] [PMID: 17308309]

[123]
John, A.; Reddy, P.H. Synaptic basis of Alzheimer’s disease: Focus on synaptic amyloid β, P-tau and mitochondria. Ageing Res. Rev.,  2021, 65, 101208.
 [http://dx.doi.org/10.1016/j.arr.2020.101208] [PMID: 33157321]

[124]
Sultana, R.; Boyd-Kimball, D.; Poon, H.F.; Cai, J.; Pierce, W.M.; Klein, J.B.; Merchant, M.; Markesbery, W.R.; Butterfield, D.A. Redox proteomics identification of oxidized proteins in Alzheimer’s disease hippocampus and cerebellum: An approach to understand pathological and biochemical alterations in AD. Neurobiol. Aging,  2006, 27(11), 1564-1576.
 [http://dx.doi.org/10.1016/j.neurobiolaging.2005.09.021] [PMID: 16271804]

[125]
Resende, R.; Moreira, P.I.; Proença, T.; Deshpande, A.; Busciglio, J.; Pereira, C.; Oliveira, C.R. Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease. Free Radic. Biol. Med.,  2008, 44(12), 2051-2057.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2008.03.012] [PMID: 18423383]

[126]
Tokutake, T.; Kasuga, K.; Yajima, R.; Sekine, Y.; Tezuka, T.; Nishizawa, M.; Ikeuchi, T. Hyperphosphorylation of Tau induced by naturally secreted amyloid-β at nanomolar concentrations is modulated by insulin-dependent Akt-GSK3β signaling pathway. J. Biol. Chem.,  2012, 287(42), 35222-35233.
 [http://dx.doi.org/10.1074/jbc.M112.348300] [PMID: 22910909]

[127]
Wu, H.Y.; Kuo, P.C.; Wang, Y.T.; Lin, H.T.; Roe, A.D.; Wang, B.Y.; Han, C.L.; Hyman, B.T.; Chen, Y.J.; Tai, H.C. β-Amyloid induces pathology-related patterns of tau hyperphosphorylation at synaptic terminals. J. Neuropathol. Exp. Neurol.,  2018, 77(9), 814-826.
 [http://dx.doi.org/10.1093/jnen/nly059] [PMID: 30016458]

[128]
Zhang, H.; Wei, W.; Zhao, M.; Ma, L.; Jiang, X.; Pei, H.; Cao, Y.; Li, H. Interaction between Aβ and tau in the pathogenesis of Alzheimer’s disease. Int. J. Biol. Sci.,  2021, 17(9), 2181-2192.
 [http://dx.doi.org/10.7150/ijbs.57078] [PMID: 34239348]

[129]
Zhang, L.; Liang, X.; Zhang, Z.; Luo, H. Cerebrospinal fluid and blood biomarkers in the diagnostic assays of Alzheimer’s disease. J. Innov. Opt. Health Sci.,  2022, 15(1), 2230001.
 [http://dx.doi.org/10.1142/S1793545822300014]

[130]
Alavi Naini, S.M.; Soussi-Yanicostas, N. Tau hyperphosphorylation and oxidative stress, a critical vicious circle in neurodegenerative tauopathies? Oxid. Med. Cell. Longev.,  2015, 2015, 1-17.
 [http://dx.doi.org/10.1155/2015/151979] [PMID: 26576216]

[131]
Su, B.; Wang, X.; Lee, H.; Tabaton, M.; Perry, G.; Smith, M.A.; Zhu, X. Chronic oxidative stress causes increased tau phosphorylation in M17 neuroblastoma cells. Neurosci. Lett.,  2010, 468(3), 267-271.
 [http://dx.doi.org/10.1016/j.neulet.2009.11.010] [PMID: 19914335]

[132]
Ibáñez-Salazar, A.; Bañuelos-Hernández, B.; Rodríguez-Leyva, I.; Chi-Ahumada, E.; Monreal-Escalante, E.; Jiménez-Capdeville, M.E.; Rosales-Mendoza, S. Oxidative stress modifies the levels and phosphorylation state of tau protein in human fibroblasts. Front. Neurosci.,  2017, 11, 495.
 [http://dx.doi.org/10.3389/fnins.2017.00495] [PMID: 28936161]

[133]
Lovell, M.A.; Xiong, S.; Xie, C.; Davies, P.; Markesbery, W.R. Induction of hyperphosphorylated tau in primary rat cortical neuron cultures mediated by oxidative stress and glycogen synthase kinase-3. J. Alzheimers Dis.,  2005, 6(6), 659-671.
 [http://dx.doi.org/10.3233/JAD-2004-6610] [PMID: 15665406]

[134]
Melov, S.; Adlard, P.A.; Morten, K.; Johnson, F.; Golden, T.R.; Hinerfeld, D.; Schilling, B.; Mavros, C.; Masters, C.L.; Volitakis, I.; Li, Q.X.; Laughton, K.; Hubbard, A.; Cherny, R.A.; Gibson, B.; Bush, A.I. Mitochondrial oxidative stress causes hyperphosphorylation of tau. PLoS One,  2007, 2(6), e536.
 [http://dx.doi.org/10.1371/journal.pone.0000536] [PMID: 17579710]

[135]
Haque, M.M.; Murale, D.P.; Kim, Y.K.; Lee, J.S. Crosstalk between oxidative stress and tauopathy. Int. J. Mol. Sci.,  2019, 20(8), 1959.
 [http://dx.doi.org/10.3390/ijms20081959] [PMID: 31013607]

[136]
Atlante, A.; Valenti, D.; Latina, V.; Amadoro, G. Role of oxygen radicals in alzheimer’s disease: Focus on tau protein. Oxygen,  2021, 1(2), 96-120.
 [http://dx.doi.org/10.3390/oxygen1020010]

[137]
Esteras, N.; Kundel, F.; Amodeo, G.F.; Pavlov, E.V.; Klenerman, D.; Abramov, A.Y. Insoluble tau aggregates induce neuronal death through modification of membrane ion conductance, activation of voltage‐gated calcium channels and NADPH oxidase. FEBS J.,  2021, 288(1), 127-141.
 [http://dx.doi.org/10.1111/febs.15340] [PMID: 32338825]

[138]
Liu, Z.; Li, P.; Wu, J.; Wang, Y.; Li, P.; Hou, X. The cascade of oxidative stress and tau protein autophagic dysfunction in alzheimer’s disease. In: Alzheimer’s Dis Challenges Future, 2; InTech, 2015. 
 [http://dx.doi.org/10.5772/59980]

[139]
Yoshiyama, Y.; Lee, V.M.Y.; Trojanowski, J.Q. Therapeutic strategies for tau mediated neurodegeneration. J. Neurol. Neurosurg. Psychiatry,  2013, 84(7), 784-795.
 [http://dx.doi.org/10.1136/jnnp-2012-303144] [PMID: 23085937]

[140]
Cunningham, D.; DeBarber, A.E.; Bir, N.; Binkley, L.; Merkens, L.S.; Steiner, R.D.; Herman, G.E. Analysis of hedgehog signaling in cerebellar granule cell precursors in a conditional Nsdhl allele demonstrates an essential role for cholesterol in postnatal CNS development. Hum. Mol. Genet.,  2015, 24(10), 2808-2825.
 [http://dx.doi.org/10.1093/hmg/ddv042] [PMID: 25652406]

[141]
Hussain, G.; Wang, J.; Rasul, A.; Anwar, H.; Imran, A.; Qasim, M.; Zafar, S.; Kamran, S.K.S.; Razzaq, A.; Aziz, N.; Ahmad, W.; Shabbir, A.; Iqbal, J.; Baig, S.M.; Sun, T. Role of cholesterol and sphingolipids in brain development and neurological diseases. Lipids Health Dis.,  2019, 18(1), 26.
 [http://dx.doi.org/10.1186/s12944-019-0965-z] [PMID: 30683111]

[142]
Qian, L.; Chai, A.B.; Gelissen, I.C.; Brown, A.J. Balancing cholesterol in the brain: From synthesis to disposal. Exploration of Neuroprotective Therapy,  2022, 2, 1-27.
 [http://dx.doi.org/10.37349/ent.2022.00015]

[143]
Mahley, R.W. Central nervous system lipoproteins: ApoE and regulation of cholesterol metabolism. Arterioscler. Thromb. Vasc. Biol.,  2016, 36(7), 1305-1315.
 [http://dx.doi.org/10.1161/ATVBAHA.116.307023] [PMID: 27174096]

[144]
Wood, W.G.; Li, L.; Müller, W.E.; Eckert, G.P. Cholesterol as a causative factor in Alzheimer’s disease: A debatable hypothesis. J. Neurochem.,  2014, 129(4), 559-572.
 [http://dx.doi.org/10.1111/jnc.12637] [PMID: 24329875]

[145]
Popugaeva, E.; Pchitskaya, E.; Bezprozvanny, I. Dysregulation of intracellular calcium signaling in Alzheimer’s disease. Antioxid. Redox Signal.,  2018, 29(12), 1176-1188.
 [http://dx.doi.org/10.1089/ars.2018.7506] [PMID: 29890840]

[146]
Kodis, E.J.; Choi, S.; Swanson, E.; Ferreira, G.; Bloom, G.S. N‐methyl‐D‐aspartate receptor–mediated calcium influx connects amyloid‐β oligomers to ectopic neuronal cell cycle reentry in Alzheimer’s disease. Alzheimers Dement.,  2018, 14(10), 1302-1312.
 [http://dx.doi.org/10.1016/j.jalz.2018.05.017] [PMID: 30293574]

[147]
Chung, J.; Phukan, G.; Vergote, D.; Mohamed, A.; Maulik, M.; Stahn, M. Endosomal-lysosomal cholesterol sequestration by U18666A differentially regulates APP metabolism in normal and APP overexpressing cells. Mol. Cell. Biol.,  2018, 38(11), 529-517.

[148]
Oveisgharan, S.; Buchman, A.S.; Yu, L.; Farfel, J.; Hachinski, V.; Gaiteri, C.; De Jager, P.L.; Schneider, J.A.; Bennett, D.A. APOE ε2ε4 genotype, incident AD and MCI, cognitive decline, and AD pathology in older adults. Neurology,  2018, 90(24), e2119-e2126.
 [http://dx.doi.org/10.1212/WNL.0000000000005677]

[149]
Li, Z.; Shue, F.; Zhao, N.; Shinohara, M.; Bu, G. APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease. Mol. Neurodegener.,  2020, 15(1), 63.
 [http://dx.doi.org/10.1186/s13024-020-00413-4] [PMID: 33148290]

[150]
Gamba, P.; Testa, G.; Sottero, B.; Gargiulo, S.; Poli, G.; Leonarduzzi, G. The link between altered cholesterol metabolism and Alzheimer’s disease. Ann. N. Y. Acad. Sci.,  2012, 1259(1), 54-64.
 [http://dx.doi.org/10.1111/j.1749-6632.2012.06513.x] [PMID: 22758637]

[151]
Shang, J.; Yamashita, T.; Fukui, Y.; Song, D.; Li, X.; Zhai, Y.; Nakano, Y.; Morihara, R.; Hishikawa, N.; Ohta, Y.; Abe, K. Different associations of plasma biomarkers in alzheimer’s disease, mild cognitive impairment, vascular dementia, and ischemic stroke. J. Clin. Neurol.,  2018, 14(1), 29-34.
 [http://dx.doi.org/10.3988/jcn.2018.14.1.29] [PMID: 29629537]

[152]
Catapano, A.L. Atherogenic lipoproteins as treatment targets. Nat. Rev. Cardiol.,  2018, 15(2), 75-76.
 [http://dx.doi.org/10.1038/nrcardio.2017.221] [PMID: 29336436]

[153]
Fenyvesi, F.; Fenyvesi, É.; Szente, L.; Goda, K.; Bacsó, Z.; Bácskay, I.; Váradi, J.; Kiss, T.; Molnár, É.; Janáky, T.; Szabó, G., Jr; Vecsernyés, M. P-glycoprotein inhibition by membrane cholesterol modulation. Eur. J. Pharm. Sci.,  2008, 34(4-5), 236-242.
 [http://dx.doi.org/10.1016/j.ejps.2008.04.005] [PMID: 18539442]

[154]
Troost, J.; Lindenmaier, H.; Haefeli, W.E.; Weiss, J. Modulation of cellular cholesterol alters P-glycoprotein activity in multidrug-resistant cells. Mol. Pharmacol.,  2004, 66(5), 1332-1339.
 [http://dx.doi.org/10.1124/mol.104.002329] [PMID: 15308763]

[155]
Radeva, G.; Perabo, J.; Sharom, F.J. P‐Glycoprotein is localized in intermediate‐density membrane microdomains distinct from classical lipid rafts and caveolar domains. FEBS J.,  2005, 272(19), 4924-4937.
 [http://dx.doi.org/10.1111/j.1742-4658.2005.04905.x] [PMID: 16176266]

[156]
Tarling, E.J.; Vallim, T.Q.A.; Edwards, P.A. Role of ABC transporters in lipid transport and human disease. Trends Endocrinol. Metab.,  2013, 24(7), 342-350.
 [http://dx.doi.org/10.1016/j.tem.2013.01.006] [PMID: 23415156]

[157]
Hochman, J.H.; Pudvah, N.; Qiu, J.; Yamazaki, M.; Tang, C.; Lin, J.H.; Prueksaritanont, T. Interactions of human P-glycoprotein with simvastatin, simvastatin acid, and atorvastatin. Pharm. Res.,  2004, 21(9), 1686-1691.
 [http://dx.doi.org/10.1023/B:PHAM.0000041466.84653.8c] [PMID: 15497697]

[158]
Holtzman, C.W.; Wiggins, B.S.; Spinler, S.A. Role of P-glycoprotein in statin drug interactions. Pharmacotherapy,  2006, 26(11), 1601-1607.
 [http://dx.doi.org/10.1592/phco.26.11.1601] [PMID: 17064205]

[159]
Bogman, K.; Peyer, A.K.; Török, M.; Küsters, E.; Drewe, J. HMG‐CoA reductase inhibitors and P‐glycoprotein modulation. Br. J. Pharmacol.,  2001, 132(6), 1183-1192.
 [http://dx.doi.org/10.1038/sj.bjp.0703920] [PMID: 11250868]

[160]
Shepardson, N.E.; Shankar, G.M.; Selkoe, D.J. Cholesterol level and statin use in Alzheimer disease: II. Review of human trials and recommendations. Arch. Neurol.,  2011, 68(11), 1385-1392.
 [http://dx.doi.org/10.1001/archneurol.2011.242] [PMID: 22084122]

[161]
Rehakova, R.; Cebova, M.; Matuskova, Z.; Kosutova, M.; Kovacsova, M.; Pechanova, O.G. Brain cholesterol and the role of statins in neuroprotection. Act. Nerv. Super Rediviva,  2016, 58(1), 11-17.

[162]
Lushchak, V.I.; Duszenko, M.; Gospodaryov, D.V.; Garaschuk, O. Oxidative stress and energy metabolism in the brain: Midlife as a turning point. Antioxidants,  2021, 10(11), 1715.
 [http://dx.doi.org/10.3390/antiox10111715] [PMID: 34829586]

[163]
Kaya, M.; Ahishali, B. Basic physiology of the blood-brain barrier in health and disease: A brief overview. Tissue Barriers,  2021, 9(1), 1840913.
 [http://dx.doi.org/10.1080/21688370.2020.1840913] [PMID: 33190576]

[164]
Singh, A.; Kukreti, R.; Saso, L.; Kukreti, S. Oxidative stress: A key modulator in neurodegenerative diseases. Molecules,  2019, 24(8), 1583.
 [http://dx.doi.org/10.3390/molecules24081583] [PMID: 31013638]

[165]
Kwon, H.S.; Koh, S.H. Neuroinflammation in neurodegenerative disorders: The roles of microglia and astrocytes. Transl. Neurodegener.,  2020, 9(1), 42.
 [http://dx.doi.org/10.1186/s40035-020-00221-2] [PMID: 33239064]

[166]
Rizzo, M.T.; Saquib, M.; Leaver, H.A. Oxidative stress and brain endothelial cells. Systems biology of free radicals and antioxidants; Laher, I., Ed.; , 2014, pp. 1959-1977.
 [http://dx.doi.org/10.1007/978-3-642-30018-9_93]

[167]
Costea, L.; Mészáros, Á.; Bauer, H.; Bauer, H.C.; Traweger, A.; Wilhelm, I.; Farkas, A.E.; Krizbai, I.A. The blood–brain barrier and its intercellular junctions in age-related brain disorders. Int. J. Mol. Sci.,  2019, 20(21), 5472.
 [http://dx.doi.org/10.3390/ijms20215472] [PMID: 31684130]

[168]
Sita, G.; Hrelia, P.; Tarozzi, A.; Morroni, F. P-glycoprotein (ABCB1) and oxidative stress: focus on Alzheimer’s disease. Oxid. Med. Cell. Longev.,  2017, 2017, 1-13.
 [http://dx.doi.org/10.1155/2017/7905486] [PMID: 29317984]

[169]
Miller, D.S. Regulation of ABC transporters at the blood–brain barrier. Clin. Pharmacol. Ther.,  2015, 97(4), 395-403.
 [http://dx.doi.org/10.1002/cpt.64] [PMID: 25670036]

[170]
Huls, M.; Russel, F.G.M.; Masereeuw, R. The role of ATP binding cassette transporters in tissue defense and organ regeneration. J. Pharmacol. Exp. Ther.,  2009, 328(1), 3-9.
 [http://dx.doi.org/10.1124/jpet.107.132225] [PMID: 18791064]

[171]
Hartz, A.M.S.; Miller, D.S.; Bauer, B. Restoring blood-brain barrier P-glycoprotein reduces brain amyloid-β in a mouse model of Alzheimer’s disease. Mol. Pharmacol.,  2010, 77(5), 715-723.
 [http://dx.doi.org/10.1124/mol.109.061754] [PMID: 20101004]

[172]
Guo, J.; Huang, X.; Dou, L.; Yan, M.; Shen, T.; Tang, W.; Li, J. Aging and aging-related diseases: From molecular mechanisms to interventions and treatments. Signal Transduct. Target. Ther.,  2022, 7(1), 391.
 [http://dx.doi.org/10.1038/s41392-022-01251-0] [PMID: 36522308]

[173]
Abuznait, A.H.; Cain, C.; Ingram, D.; Burk, D.; Kaddoumi, A. Up-regulation of P-glycoprotein reduces intracellular accumulation of beta amyloid: investigation of P-glycoprotein as a novel therapeutic target for Alzheimer’s disease. J. Pharm. Pharmacol.,  2011, 63(8), 1111-1118.
 [http://dx.doi.org/10.1111/j.2042-7158.2011.01309.x] [PMID: 21718295]

[174]
Demeule, M.; Régina, A.; Jodoin, J.; Laplante, A.; Dagenais, C.; Berthelet, F.; Moghrabi, A.; Béliveau, R. Drug transport to the brain: Key roles for the efflux pump P-glycoprotein in the blood–brain barrier. Vascul. Pharmacol.,  2002, 38(6), 339-348.
 [http://dx.doi.org/10.1016/S1537-1891(02)00201-X] [PMID: 12529928]

[175]
Tsuji, A. Influx transporters and drug targeting: Application of peptide and cation transporters. In: International Congress Series; Elsevier, 2005; 1277, pp. 75-84.
 [http://dx.doi.org/10.1016/j.ics.2005.02.013]

[176]
Prachayasittikul, V. P-glycoprotein transporter in drug development. EXCLI J.,  2016, 15, 113-118.
 [PMID: 27047321]

[177]
Davis, T.P.; Sanchez-Covarubias, L.; Tome, M.E. P-glycoprotein trafficking as a therapeutic target to optimize CNS drug delivery. Adv. Pharmacol.,  2014, 71, 25-44.
 [http://dx.doi.org/10.1016/bs.apha.2014.06.009] [PMID: 25307213]

[178]
Dong, X. Current strategies for brain drug delivery. Theranostics,  2018, 8(6), 1481-1493.
 [http://dx.doi.org/10.7150/thno.21254] [PMID: 29556336]

[179]
Amin, M.L. P-glycoprotein inhibition for optimal drug delivery. Drug Target Insights,  2013, 7, 27-34.

[180]
Mitusova, K.; Peltek, O.O.; Karpov, T.E.; Muslimov, A.R.; Zyuzin, M.V.; Timin, A.S. Overcoming the blood–brain barrier for the therapy of malignant brain tumor: current status and prospects of drug delivery approaches. J. Nanobiotechnology,  2022, 20(1), 412.
 [http://dx.doi.org/10.1186/s12951-022-01610-7] [PMID: 36109754]

[181]
Ates-Alagoz, Z.; Adejare, A. Physicochemical properties for potential Alzheimer’s disease drugs. In: Drug Discovery Approaches for the Treatment of Neurodegenerative Disorders; Academic press, 2017; pp. 59-82.
 [http://dx.doi.org/10.1016/B978-0-12-802810-0.00005-2]

[182]
Wong, K.; Riaz, M.; Xie, Y.; Zhang, X.; Liu, Q.; Chen, H.; Bian, Z.; Chen, X.; Lu, A.; Yang, Z. Review of current strategies for delivering Alzheimer’s disease drugs across the blood-brain barrier. Int. J. Mol. Sci.,  2019, 20(2), 381.
 [http://dx.doi.org/10.3390/ijms20020381] [PMID: 30658419]

[183]
Spieler, D.; Namendorf, C.; Namendorf, T.; von Cube, M.; Uhr, M. Donepezil, a cholinesterase inhibitor used in Alzheimer’s disease therapy, is actively exported out of the brain by abcb1ab p-glycoproteins in mice. J. Psychiatr. Res.,  2020, 124, 29-33.
 [http://dx.doi.org/10.1016/j.jpsychires.2020.01.012] [PMID: 32114029]

[184]
Finch, A.; Pillans, P. P-glycoprotein and its role in drug-drug interactions. Aust. Prescr.,  2014, 37(4), 137-139.
 [http://dx.doi.org/10.18773/austprescr.2014.050]

[185]
Wanek, T.; Römermann, K.; Mairinger, S.; Stanek, J.; Sauberer, M.; Filip, T.; Traxl, A.; Kuntner, C.; Pahnke, J.; Bauer, F.; Erker, T.; Löscher, W.; Müller, M.; Langer, O. Factors governing P-glycoprotein-mediated drug–drug interactions at the blood–brain barrier measured with positron emission tomography. Mol. Pharm.,  2015, 12(9), 3214-3225.
 [http://dx.doi.org/10.1021/acs.molpharmaceut.5b00168] [PMID: 26202880]

[186]
Panza, F.; Lozupone, M.; Logroscino, G.; Imbimbo, B.P. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat. Rev. Neurol.,  2019, 15(2), 73-88.
 [http://dx.doi.org/10.1038/s41582-018-0116-6] [PMID: 30610216]

[187]
Loeb, M.B.; Molloy, D.W.; Smieja, M.; Standish, T.; Goldsmith, C.H.; Mahony, J.; Smith, S.; Borrie, M.; Decoteau, E.; Davidson, W.; Mcdougall, A.; Gnarpe, J.; O’donnell, M.; Chernesky, M. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer’s disease. J. Am. Geriatr. Soc.,  2004, 52(3), 381-387.
 [http://dx.doi.org/10.1111/j.1532-5415.2004.52109.x] [PMID: 14962152]

[188]
Sudsakorn, S.; Bahadduri, P.; Fretland, J.; Lu, C. 2020 FDA drug-drug interaction guidance: A comparison analysis and action plan by pharmaceutical industrial scientists. Curr. Drug Metab.,  2020, 21(6), 403-426.
 [http://dx.doi.org/10.2174/1389200221666200620210522] [PMID: 32562522]

[189]
Mohamed, L.A.; Keller, J.N.; Kaddoumi, A. Role of P-glycoprotein in mediating rivastigmine effect on amyloid-β brain load and related pathology in Alzheimer’s disease mouse model. Biochim. Biophys. Acta Mol. Basis Dis.,  2016, 1862(4), 778-787.
 [http://dx.doi.org/10.1016/j.bbadis.2016.01.013] [PMID: 26780497]

[190]
Mohamed, L.A.; Qosa, H.; Kaddoumi, A. Age-related decline in brain and hepatic clearance of amyloid-beta is rectified by the cholinesterase inhibitors donepezil and rivastigmine in rats. ACS Chem. Neurosci.,  2015, 6(5), 725-736.
 [http://dx.doi.org/10.1021/acschemneuro.5b00040] [PMID: 25782004]

[191]
Qosa, H.; Abuznait, A.H.; Hill, R.A.; Kaddoumi, A. Enhanced brain amyloid-β clearance by rifampicin and caffeine as a possible protective mechanism against Alzheimer’s disease. J. Alzheimers Dis.,  2012, 31(1), 151-165.
 [http://dx.doi.org/10.3233/JAD-2012-120319] [PMID: 22504320]

[192]
Umeda, T.; Tanaka, A.; Sakai, A.; Yamamoto, A.; Sakane, T.; Tomiyama, T. Intranasal rifampicin for Alzheimer’s disease prevention. Alzheimers Dement.,  2018, 4(1), 304-313.
 [http://dx.doi.org/10.1016/j.trci.2018.06.012] [PMID: 30094330]

[193]
Washington, C.B.; Duran, G.E.; Man, M.C.; Sikic, B.I.; Blaschke, T.F. Interaction of anti-HIV protease inhibitors with the multidrug transporter P-glycoprotein (P-gp) in human cultured cells. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol.,  1998, 19(3), 203-209.

[194]
Vourvahis, M.; Dumond, J.; Patterson, K. Effects of tipranavir/ritonavir (TPV/r) on the activity of hepatic and intestinal cytochrome. 14th Conference on Retroviruses and Opportunistic Infections,  2007, p. 450.Los Angeles

[195]
Narang, V.S.; Fraga, C.; Kumar, N.; Shen, J.; Throm, S.; Stewart, C.F.; Waters, C.M. Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood-brain barrier. Am. J. Physiol. Cell Physiol.,  2008, 295(2), C440-C450.
 [http://dx.doi.org/10.1152/ajpcell.00491.2007] [PMID: 18524938]

[196]
Iqbal, M.; Baello, S.; Javam, M.; Audette, M.C.; Gibb, W.; Matthews, S.G. Regulation of multidrug resistance p‐glycoprotein in the developing blood–brain barrier: Interplay between glucocorticoids and cytokines. J. Neuroendocrinol.,  2016, 28(3), jne.12360.
 [http://dx.doi.org/10.1111/jne.12360] [PMID: 26718627]

[197]
Yang, H.; Liu, H.; Liu, X.; Zhang, D.; Liu, Y.; Liu, X.; Wang, G.; Xie, L. Increased P-glycoprotein function and level after long-term exposure of four antiepileptic drugs to rat brain microvascular endothelial cells in vitro. Neurosci. Lett.,  2008, 434(3), 299-303.
 [http://dx.doi.org/10.1016/j.neulet.2008.01.071] [PMID: 18313849]

[198]
Owen, A.; Goldring, C.; Morgan, P.; Park, B.K.; Pirmohamed, M. Induction of P‐glycoprotein in lymphocytes by carbamazepine and rifampicin: the role of nuclear hormone response elements. Br. J. Clin. Pharmacol.,  2006, 62(2), 237-242.
 [http://dx.doi.org/10.1111/j.1365-2125.2006.02587.x] [PMID: 16842400]

[199]
Ke, X.; Cheng, Y.; Yu, N.; Di, Q. Effects of carbamazepine on the P-gp and CYP3A expression correlated with PXR or NF-κB activity in the bEnd.3 cells. Neurosci. Lett.,  2019, 690, 48-55.
 [http://dx.doi.org/10.1016/j.neulet.2018.10.016] [PMID: 30312753]

[200]
Störmer, E.; von Moltke, L.L.; Perloff, M.D.; Greenblatt, D.J. P-glycoprotein interactions of nefazodone and trazodone in cell culture. J. Clin. Pharmacol.,  2001, 41(7), 708-714.
 [http://dx.doi.org/10.1177/00912700122010609] [PMID: 11452702]

[201]
Shirasaka, Y.; Kawasaki, M.; Sakane, T.; Omatsu, H.; Moriya, Y.; Nakamura, T.; Sakaeda, T.; Okumura, K.; Langguth, P.; Yamashita, S. Induction of human P-glycoprotein in Caco-2 cells: Development of a highly sensitive assay system for P-glycoprotein-mediated drug transport. Drug Metab. Pharmacokinet.,  2006, 21(5), 414-423.
 [http://dx.doi.org/10.2133/dmpk.21.414] [PMID: 17072095]

[202]
Harmsen, S.; Meijerman, I.; Febus, C.L.; Maas-Bakker, R.F.; Beijnen, J.H.; Schellens, J.H.M. PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line. Cancer Chemother. Pharmacol.,  2010, 66(4), 765-771.
 [http://dx.doi.org/10.1007/s00280-009-1221-4] [PMID: 20041327]

[203]
Brenn, A.; Grube, M.; Jedlitschky, G.; Fischer, A.; Strohmeier, B.; Eiden, M.; Keller, M.; Groschup, M.H.; Vogelgesang, S.St. John’s Wort reduces beta-amyloid accumulation in a double transgenic Alzheimer’s disease mouse model-role of P-glycoprotein. Brain Pathol.,  2014, 24(1), 18-24.
 [http://dx.doi.org/10.1111/bpa.12069] [PMID: 23701205]

[204]
El Menuawy, A.; Brüning, T.; Eiriz, I.; Hähnel, U.; Marthe, F.; Möhle, L.; Górska, A.M.; Santos-García, I.; Wangensteen, H.; Wu, J.; Pahnke, J. Apolar extracts of St. John’s wort alleviate the effects of β-Amyloid toxicity in early alzheimer’s disease. Int. J. Mol. Sci.,  2024, 25(2), 1301.
 [http://dx.doi.org/10.3390/ijms25021301] [PMID: 38279301]

[205]
Clinical drug interaction studies: Cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry by US Food and Drug Administration. 2020. Available from: 
          https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-
       	(Accessed on December 9, 2020).

[206]
Harby, S.A.; Nassra, R.A. Memantine, as a p-glycoprotein expression modulator, enhances levetiracetam therapeutic response in epileptic patients. Asian J. Pharm. Clin. Res.,  2020, 13(5), 104-108.

[207]
Pang, X.; Wang, L.; Kang, D.; Zhao, Y.; Wu, S.; Liu, A.L.; Du, G.H. Effects of P-glycoprotein on the transport of DL0410, a potential multifunctional anti-Alzheimer agent. Molecules,  2017, 22(8), 1246.
 [http://dx.doi.org/10.3390/molecules22081246] [PMID: 28757552]

[208]
Chai, A.B.; Leung, G.K.F.; Callaghan, R.; Gelissen, I.C. P‐glycoprotein: A role in the export of amyloid‐β in Alzheimer’s disease? FEBS J.,  2020, 287(4), 612-625.
 [http://dx.doi.org/10.1111/febs.15148] [PMID: 31750987]

[209]
Wang, W.; Bodles-Brakhop, A.M.; Barger, S.W. A role for P-glycoprotein in clearance of Alzheimer amyloid β-peptide from the brain. Curr. Alzheimer Res.,  2016, 13(6), 615-620.
 [http://dx.doi.org/10.2174/1567205013666160314151012] [PMID: 26971931]

[210]
Osgood, D.; Miller, M.C.; Messier, A.A.; Gonzalez, L.; Silverberg, G.D. Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier. Neurobiol. Aging,  2017, 57, 178-185.
 [http://dx.doi.org/10.1016/j.neurobiolaging.2017.05.011] [PMID: 28654861]

[211]
Zhang, C.; Qin, H.; Zheng, R.; Wang, Y.; Yan, T.; Huan, F.; Han, Y.; Zhu, W.; Zhang, L. A new approach for Alzheimer’s disease treatment through P-gp regulation via ibuprofen. Pathol. Res. Pract.,  2018, 214(11), 1765-1771.
 [http://dx.doi.org/10.1016/j.prp.2018.08.011] [PMID: 30139557]

[212]
Zoufal, V.; Wanek, T.; Krohn, M.; Mairinger, S.; Filip, T.; Sauberer, M.; Stanek, J.; Pekar, T.; Bauer, M.; Pahnke, J.; Langer, O. Age dependency of cerebral P-glycoprotein function in wild-type and APPPS1 mice measured with PET. J. Cereb. Blood Flow Metab.,  2020, 40(1), 150-162.
 [http://dx.doi.org/10.1177/0271678X18806640] [PMID: 30354871]

[213]
Vulin, M.; Zhong, Y.; Maloney, B.J.; Bauer, B.; Hartz, A.M.S. Proteasome inhibition protects blood–brain barrier P-glycoprotein and lowers Aβ brain levels in an Alzheimer’s disease model. Fluids Barriers CNS,  2023, 20(1), 70.
 [http://dx.doi.org/10.1186/s12987-023-00470-z] [PMID: 37803468]

[214]
Pyun, J.; Koay, H.; Runwal, P.; Mawal, C.; Bush, A.I.; Pan, Y.; Donnelly, P.S.; Short, J.L.; Nicolazzo, J.A. Cu(ATSM) increases P-glycoprotein expression and function at the blood-brain barrier in C57BL6/J mice. Pharmaceutics,  2023, 15(8), 2084.
 [http://dx.doi.org/10.3390/pharmaceutics15082084] [PMID: 37631298]

[215]
Abuznait, A.H.; Kaddoumi, A. Role of ABC transporters in the pathogenesis of Alzheimer’s disease. ACS Chem. Neurosci.,  2012, 3(11), 820-831.
 [http://dx.doi.org/10.1021/cn300077c] [PMID: 23181169]

[216]
Bello, I.; Salerno, M. Evidence against a role of P-glycoprotein in the clearance of the Alzheimer’s disease Aβ1–42 peptides. Cell Stress Chaperones,  2015, 20(3), 421-430.
 [http://dx.doi.org/10.1007/s12192-014-0566-8] [PMID: 25591827]

[217]
Nazer, B.; Hong, S.; Selkoe, D.J. LRP promotes endocytosis and degradation, but not transcytosis, of the amyloid-β peptide in a blood–brain barrier in vitro model. Neurobiol. Dis.,  2008, 30(1), 94-102.
 [http://dx.doi.org/10.1016/j.nbd.2007.12.005] [PMID: 18289866]

[218]
Tai, L.M.; Loughlin, A.J.; Male, D.K.; Romero, I.A. P-glycoprotein and breast cancer resistance protein restrict apical-to-basolateral permeability of human brain endothelium to amyloid-beta. J. Cereb. Blood Flow Metab.,  2009, 29(6), 1079-1083.
 [http://dx.doi.org/10.1038/jcbfm.2009.42] [PMID: 19367293]

[219]
Arduino, I.; Iacobazzi, R.M.; Riganti, C.; Lopedota, A.A.; Perrone, M.G.; Lopalco, A.; Cutrignelli, A.; Cantore, M.; Laquintana, V.; Franco, M.; Colabufo, N.A.; Luurtsema, G.; Contino, M.; Denora, N. Induced expression of P-gp and BCRP transporters on brain endothelial cells using transferrin functionalized nanostructured lipid carriers: A first step of a potential strategy for the treatment of Alzheimer’s disease. Int. J. Pharm.,  2020, 591, 120011.
 [http://dx.doi.org/10.1016/j.ijpharm.2020.120011] [PMID: 33115695]

[220]
Chai, A.B.; Callaghan, R.; Gelissen, I.C. The ubiquitin E3 ligase Nedd4 regulates the expression and amyloid-β Peptide export activity of p-glycoprotein. Int. J. Mol. Sci.,  2022, 23(3), 1019.
 [http://dx.doi.org/10.3390/ijms23031019] [PMID: 35162941]

[221]
Aquino, G.V.; Dabi, A.; Odom, G.J.; Lavado, R.; Nunn, K.; Thomas, K.; Bruce, E.D. Evaluating the effect of acute diesel exhaust particle exposure on p-glycoprotein efflux transporter in the blood-brain barrier co-cultured with microglia. Curr. Res. Toxicol.,  2023, 4, 100107.

[222]
Alkhalifa, A.E.; Al-Ghraiybah, N.F.; Odum, J.; Shunnarah, J.G.; Austin, N.; Kaddoumi, A. Blood–brain barrier breakdown in Alzheimer’s disease: Mechanisms and targeted strategies. Int. J. Mol. Sci.,  2023, 24(22), 16288.
 [http://dx.doi.org/10.3390/ijms242216288] [PMID: 38003477]

[223]
Bartels, A.L.; Kortekaas, R.; Bart, J.; Willemsen, A.T.M.; de Klerk, O.L.; de Vries, J.J.; van Oostrom, J.C.H.; Leenders, K.L. Blood–brain barrier P-glycoprotein function decreases in specific brain regions with aging: A possible role in progressive neurodegeneration. Neurobiol. Aging,  2009, 30(11), 1818-1824.
 [http://dx.doi.org/10.1016/j.neurobiolaging.2008.02.002] [PMID: 18358568]

[224]
Wijesuriya, H.C.; Bullock, J.Y.; Faull, R.L.M.; Hladky, S.B.; Barrand, M.A. ABC efflux transporters in brain vasculature of Alzheimer’s subjects. Brain Res.,  2010, 1358, 228-238.
 [http://dx.doi.org/10.1016/j.brainres.2010.08.034] [PMID: 20727860]

[225]
Jeynes, B.; Provias, J. An investigation into the role of P-glycoprotein in Alzheimer’s disease lesion pathogenesis. Neurosci. Lett.,  2011, 487(3), 389-393.
 [http://dx.doi.org/10.1016/j.neulet.2010.10.063] [PMID: 21047545]

[226]
van Assema, D.M.E.; Lubberink, M.; Bauer, M.; van der Flier, W.M.; Schuit, R.C.; Windhorst, A.D.; Comans, E.F.I.; Hoetjes, N.J.; Tolboom, N.; Langer, O.; Müller, M.; Scheltens, P.; Lammertsma, A.A.; van Berckel, B.N.M. Blood–brain barrier P-glycoprotein function in Alzheimer’s disease. Brain,  2012, 135(1), 181-189.
 [http://dx.doi.org/10.1093/brain/awr298] [PMID: 22120145]

[227]
Jeynes, B.; Provias, J. P-glycoprotein altered expression in Alzheimer’s disease: Regional anatomic variability. J. Neurodegener. Dis.,  2013, 2013, 1-7.
 [http://dx.doi.org/10.1155/2013/257953] [PMID: 26316985]

[228]
Chiu, C.; Miller, M.C.; Monahan, R.; Osgood, D.P.; Stopa, E.G.; Silverberg, G.D. P-glycoprotein expression and amyloid accumulation in human aging and Alzheimer’s disease: Preliminary observations. Neurobiol. Aging,  2015, 36(9), 2475-2482.
 [http://dx.doi.org/10.1016/j.neurobiolaging.2015.05.020] [PMID: 26159621]

[229]
Bruckmann, S.; Brenn, A.; Grube, M.; Niedrig, K.; Holtfreter, S. von Bohlen und Halbach, O.; Groschup, M.; Keller, M.; Vogelgesang, S. Lack of P-glycoprotein results in impairment of removal of beta-amyloid and increased intraparenchymal cerebral amyloid angiopathy after active immunization in a transgenic mouse model of Alzheimer’s disease. Curr. Alzheimer Res.,  2017, 14(6), 656-667.
 [http://dx.doi.org/10.2174/1567205013666161201201227] [PMID: 27915995]

[230]
Kannan, P.; Schain, M.; Kretzschmar, W.W.; Weidner, L.; Mitsios, N.; Gulyás, B.; Blom, H.; Gottesman, M.M.; Innis, R.B.; Hall, M.D.; Mulder, J. An automated method measures variability in P-glycoprotein and ABCG2 densities across brain regions and brain matter. J. Cereb. Blood Flow Metab.,  2017, 37(6), 2062-2075.
 [http://dx.doi.org/10.1177/0271678X16660984] [PMID: 27488911]

[231]
Storelli, F.; Billington, S.; Kumar, A.R.; Unadkat, J.D. Abundance of P‐glycoprotein and other drug transporters at the human blood‐brain barrier in alzheimer’s disease: A quantitative targeted proteomic study. Clin. Pharmacol. Ther.,  2021, 109(3), 667-675.
 [http://dx.doi.org/10.1002/cpt.2035] [PMID: 32885413]

[232]
van Assema, D.M.E.; Lubberink, M.; Rizzu, P.; van Swieten, J.C.; Schuit, R.C.; Eriksson, J.; Scheltens, P.; Koepp, M.; Lammertsma, A.A.; van Berckel, B.N.M. Blood–brain barrier P-glycoprotein function in healthy subjects and Alzheimer’s disease patients: Effect of polymorphisms in the ABCB1 gene. EJNMMI Res.,  2012, 2(1), 57.
 [http://dx.doi.org/10.1186/2191-219X-2-57] [PMID: 23067778]

[233]
Zhong, X.; Liu, M.Y.; Sun, X.H.; Wei, M.J. Association between ABCB1 polymorphisms and haplotypes and Alzheimer’s disease: A meta-analysis. Sci. Rep.,  2016, 6(1), 32708-32708.
 [http://dx.doi.org/10.1038/srep32708] [PMID: 27600024]

[234]
Fehér, Á.; Juhász, A.; Pákáski, M.; Kálmán, J.; Janka, Z. ABCB1 C3435T polymorphism influences the risk for Alzheimer’s disease. J. Mol. Neurosci.,  2014, 54(4), 826-829.
 [http://dx.doi.org/10.1007/s12031-014-0427-z] [PMID: 25273678]

[235]
Guinchat, V.; Ansermot, N.; Ing Lorenzini, K.; Politis, D.; Daali, Y.; Eap, C.B.; Crettol, S. Case report: Opioid use disorder associated with low/moderate dose of loperamide in an intellectual disability patient with CYP3A and P-Glycoprotein reduced activity. Front. Psychiatry,  2022, 13, 910684.
 [http://dx.doi.org/10.3389/fpsyt.2022.910684] [PMID: 35815036]

[236]
P-glycoprotein function in brain diseases, Identifier NCT00677885. Sponsor national institute of mental health (NIMH), information provided by national institutes of health clinical center.  2014. Available from:
          https://clinicaltrials.gov/study/NCT00677885(Accessed 2019-11-22). 

[237]
Mossel, P.; Garcia Varela, L.; Arif, W.M.; van der Weijden, C.W.J.; Boersma, H.H.; Willemsen, A.T.M.; Boellaard, R.; Elsinga, P.H.; Borra, R.J.H.; Colabufo, N.A.; Toyohara, J.; de Deyn, P.P.; Dierckx, R.A.J.O.; Lammertsma, A.A.; Bartels, A.L.; Luurtsema, G. Evaluation of P-glycoprotein function at the blood–brain barrier using [18F]MC225-PET. Eur. J. Nucl. Med. Mol. Imaging,  2021, 48(12), 4105-4106.
 [http://dx.doi.org/10.1007/s00259-021-05419-8] [PMID: 34089347]

[238]
García-Varela, L.; Rodríguez-Pérez, M.; Custodia, A.; Moraga-Amaro, R.; Colabufo, N.A.; Aguiar, P.; Sobrino, T.; Dierckx, R.A.J.O.; van Waarde, A.; Elsinga, P.H.; Luurtsema, G. In vivo induction of P-glycoprotein function can be measured with [18F] MC225 and PET. Mol. Pharm.,  2021, 18(8), 3073-3085.
 [http://dx.doi.org/10.1021/acs.molpharmaceut.1c00302] [PMID: 34228458]

[239]
MC225-PET in neurodegenerative disease, identifier NCT05853471. Sponsor national institute of mental health (nimh), information provided by national institutes of health clinical center. 2022. Available from:  https://classic.clinicaltrials.gov/ct2/show/NCT05853471(Accessed 2023-5-10).

[240]
Bors, L.; Erdő, F. Overcoming the blood–brain barrier. Challenges and tricks for CNS drug delivery. Sci. Pharm.,  2019, 87(1), 6.
 [http://dx.doi.org/10.3390/scipharm87010006]
Rights & Permissions Print Cite
Article Metrics
11
1
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/0115701808293022240216070603	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X
Letters in Drug Design & Discovery

P-glycoproteins in the Pathology and Treatment of Alzheimer's Disease

Abstract

Graphical Abstract

Related Journals

Related Books

Related Articles
